Specific changes in sleep oscillations after blocking human metabotropic glutamate receptor 5 in the absence of altered memory function

Background: Sleep consolidates declarative memory by repeated replay linked to the cardinal oscillations of non-rapid eye movement (NonREM) sleep. However, there is so far little evidence of classical glutamatergic plasticity induced by this replay. Rather, we have previously reported that blocking N-methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors does not affect sleep-dependent consolidation of declarative memory. Aims: The aim of this study was to investigate the role of metabotropic glutamate receptor 5 (mGluR5) in memory processing during sleep. Methods: In two placebo-controlled within-subject crossover experiments with 20 healthy humans each, we used fenobam to block mGluR5 during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) in the evening, then received the drug and recall was tested the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II participants learned new word-pairs in the morning after sleep. Results/outcomes: Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12–15 Hz spindles but augmented 2–4 Hz delta waves, whereas in rapid eye movement (REM) sleep it suppressed 4–8 Hz theta and 16–22 Hz beta waves. Notably, under fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Conclusions/interpretations: Our findings indicate that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations.

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Specific changes in sleep oscillations after blocking human metabotropic glutamate receptor 5 in the absence of altered memory function

10.1101/2020.07.24.219865 ◽

2020 ◽

Author(s):

Gordon B. Feld ◽

Til Ole Bergmann ◽

Marjan Alizadeh-Asfestani ◽

Viola Stuke ◽

Jan-Philipp Wriede ◽

...

Keyword(s):

Glutamate Receptor ◽

Ampa Receptors ◽

Metabotropic Glutamate Receptor ◽

Declarative Memory ◽

Memory Function ◽

Metabotropic Glutamate Receptor 5 ◽

Metabotropic Glutamate ◽

Healthy Humans ◽

Procedural Task ◽

Nonrem Sleep

AbstractSleep consolidates declarative memory by the repeated replay of neuronal traces encoded during prior wakefulness. This replay during sleep is linked to the cardinal oscillations of NonREM sleep. Although this replay is ideally suited to support plasticity, there is so far little evidence of classical glutamatergic plasticity playing a role in this process. To the contrary, we have previously reported that blocking NMDA or AMPA receptors does not affect sleep-dependent consolidation of declarative memory. Here, in two placebo-controlled within-subject cross-over experiments with 20 healthy humans each, we used fenobam to block metabotropic glutamate receptor 5 (mGluR5) during sleep. In Experiment I, participants learned word-pairs (declarative task) and a finger sequence (procedural task) during the evening before being administered the treatment and then sleeping for 8 hours – recall was tested in the next morning. To cover possible effects on synaptic renormalization processes during sleep, in Experiment II, participants learned new word-pairs in the morning after sleep. Surprisingly, fenobam neither reduced retention of memory across sleep nor new learning after sleep, although it severely altered sleep architecture and memory-relevant EEG oscillations. In NonREM sleep, fenobam suppressed 12-15 Hz spindles but augmented 2-4 Hz delta waves, whereas in REM sleep it suppressed 4-8 Hz theta and 16-22 Hz beta waves. Notably, under Fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Our findings indicates that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations.

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